Preterm Birth and PPROM - Vanderbilt University Medical · PDF filepathway and not mechanism...
Transcript of Preterm Birth and PPROM - Vanderbilt University Medical · PDF filepathway and not mechanism...
Advances in preterm birth prevention: Impact on PPROM management
Amy P. Murtha, MD
Associate Professor
Duke University Medical Center
Outline
Overview Preterm birth
Focus on PTL and PPROM
Differences in clinical phenotype
Latest advances in treatment/diagnostics
Focus on progesterone therapy
Diagnosis of subclinical infection
Preterm Birth
Preterm labor 45%
Indicated 30%
PPROM 25%
Spontaneous Preterm Birth: A Syndrome?
PTL, PPROM, and preterm cervical effacement and dilation without labor
One syndrome with multiple etiologies?
Multiple syndromes with distinct etiologies?
Categorize Spontaneous Preterm Birth
Based on presentation NOT mechanism
SPTB occurs as clinical presentation of
Infection
Vascular insult
Uterine overdistension
Stress or other pathologic processes
Syndrome with no diagnostic test/treatment
Preterm Labor ADAPTIVE
PTL is an adaptive mechanism of host defense
Eliminate fetus from hostile environment
Treatments aimed at common terminal pathway and not mechanism of disease-inducing activation will not be effective
Gabbe: Obstetrics: Normal and Problem Pregnancies, 5th ed.
Spontaneous Preterm Birth
PTL PPROM
PPROM
PPROM and Neonatal Death
California Perinatal Quality Care Collaborative
17,501 neonates at 24 -34 weeks gestations
No PPROM vs recent PPROM vs prolonged PPROM
24-26 wks prolonged PPROM associated with decreased mortality (18% vs 31%; OR 1.79; CI 1.252.56)
Membrane rupture not associated with increased neonatal mortality
Blumenfeld et al, Obstetrics & Gynecology: December 2010
Extreme PPROM
1,437 PTD at 23-27 wks; 236(16.4%) complicated by PPROM
PPROM higher rate of chorioamnionitis (33.8 vs. 17.0%; P < 0.001)
PPROM higher neonatal death at 23-24 wks (70.0 vs. 54.8%; P = 0.013)
PPROM and chorioamnionitis significant after adjusting for GA and gender (OR = 3.32; 95% CI 2.434.51, P < 0.001)
Newman et al; Archives of Gynecol and Obstet,2009
Neonatal Outcomes in PPROM
Uncomplicated PPROM (n=488) vs SPTL (n=1465) 28-34 wks
PPROM increased risk for Composite neonatal morbidity (53.7% vs 42.0%; P < .001) Mortality (1.6% vs 0.0%; P < .001) Respiratory morbidity (32.8% vs 26.4%; P = .006)
Adverse outcome more likely Latency period >7 days, oligohydramnios, male fetus, nulliparity
Prematurity-related morbidity in PPROM cannot be extrapolated from PTDs
Nir Melamed et al, Presented at SMFM 2010, Chicago
Hypothesized Mechanisms
Cervical change
Uterine Contractility
Decidual activation
Cervical Changes
Regulation of ECM composed of collagen, elastin, and fibronectin
Cervical ripening is result of
decreased collagen content
increased collagen solubility
increased collagenolytic activity
Cervical Changes
Influx of inflammatory cells into the cervical stroma
Cytokines/prostaglandins affect ECM metabolism
Influenced by estrogen and progesterone
Cervical changes are gradual over weeks
PTB often preceded by cervical ripening
Cervical Changes
ECM Remodeling Cervical Ripening
Funnelling Preterm labor
Progesterone
Uterine Contractility
Change from uncoordinated contractures to coordinated contractions
produce increase intrauterine pressure
Oxytocin important regulator of contractility
produced by decidua and hypothalamus (endocrine and paracrine)
Uterine Contractility
Gap junction formation and the expression of gap junction protein connexin 43
Similar in term and preterm labor
Progesterone, estrogen and prostaglandins implicated in gap junction formation and expression of connexin 43
Decidual Membrane Activation
PPROM membranes
Decreased collagen types I, III, and V
Structural ECM implicated in tensile strength of the membranes
Inflammation and Membrane Destruction
TNF and IL1 induce collagen remodeling and apoptosis
Apoptosis correlates directly with FM physical weakness
FM undergo remodeling resulting in weaken
Kumar , Moore; Biol of Reprod, 2006
Destruction of Chorion Cells
Apoptosis in chorion increased with chorioamnionitis (Murtha, Infect Dis OB/GYN, 2002; George, Am J Perinat, 2008)
Chorion layer thinned in PPROM (Fortner abstract #16, SMFM 2011)
PPROM Term
Recent Advances
Progesterone as a therapeutic tool for at risk individuals
Advances in molecular identification of organisms
Progesterones Role in Pregnancy
Maintains uterine quiescent
Functional progesterone withdrawal prior to labor
changes in PR-A/PR-B expression
Progesterone is an anti-inflammatory agent
Inhibits NFk which inhibits COX 2 and prostaglandin production
FM Remodeling
ECM Degradation
Decidual Activation
Uterine Contractility
PPROM PTL
Progesterone
Progesterone Progesterone
And now for something completely different!
Identifying mechanisms
resulting in SPTB
Is Subclinical Infection an etiology of PTB?
PPROM or PTL or Both?
Uncultivated Bacteria Etiology of Inflammation
AF from 46 PTB and 16 controls (term and genetic amnio)
No DNA amplified in controls
Bacterial DNA all (16/16) of culture +; (9/16) additional species
17% (5/30) of the culture - samples
Yiping et al, J of Clin Micro, January 2009
Uncultivated Bacteria Etiology of Inflammation
2/3 detected by PCR not isolated by culture
Fusobacterium nucleatum, Leptotrichia (Sneathia) spp., Bergeyella sp., Peptostreptococcus sp., Bacteroides spp., Clostridiales
PCR + had elevated AF IL-6, histological chorioamnionitis, funisitis and neonatal early-onset sepsis
Yiping et al, J of Clin Micro, January 2009
Microbes and PPROM Inflammation
PCR identified more species then culture (44 vs 14 species) included uncultivated taxa
PCR positivity associated with lower BW, higher RDS and NEC rates
Di Guilio et al, Amer J of Reprod Immun, July 2010
Commercial Break
Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)
GAPPS Mission is to Improve Birth Outcomes Worldwide by leading a collaborative, global effort to increase awareness and accelerate innovative research and interventions that will improve maternal, newborn and child health outcomes around the world.
GAPPS: Born Too Soon
Aspects of preterm birth
Priorities for action based on national, regional and global estimates
Care before and between pregnancy
Care during pregnancy and childbirth
Care for the preterm baby
GAPPS
Strategic investments in innovation and research are required to accelerate progress
Goal to cut preterm birth rate in half by 2025
Inequalities in survival rates around the world are stark:
50% of babies born at 24 wks survive in high-income countries
50% of babies born at 32 wks die in low income settings
GAPPS Projects
GAPPS- Prototypic Phenotype Classification
GAPPS Prototypic Phenotype Classification
Classification based on clinical phenotypes defined by characteristics of mother, fetus, placenta, signs of parturition or pathway to
delivery
Risk factors and mode of delivery are not included
Does not force any preterm birth into a predefined phenotype allows all relevant conditions to be part of the phenotype
Classification system will improve understanding of cause and improve surveillance across populations
GAPPS- Prototypic Phenotype Classification
5 components in a preterm birth phenotype:
1. Maternal conditions that are present before presentation for delivery
2. Fetal conditions that are present before presentation for delivery
3. Placental pathologic conditions
4. Signs of the initiation of parturition
5. Pathway to delivery
GAPPS- Prototypic Phenotype Classification
Maternal conditions Extrauterine Infection Clinical Chorioamnionitis Maternal Trauma Uterine Rupture Preeclampsia/Eclampsia
Placental Pathology Histologic Chorioamnionitis Placental Abruption Placenta Previa Other Placental Disease
Significant Fetal Conditions IUFD IUGR Abnormal FHR/BPP Infection/ Fetal Inflammatory Response Fetal Anomaly Alloimmune Fetal Anemia Polyhydramnios Multiple Fetuses
GAPPS- Prototypic Phenotype Classification
Signs of Initiation of Partuition
No Evidence of Initiation of Partuition
Evidence of Initiation of Partuition Cervical Shortening PPROM Regular Contractions Cervical Dilatation Bleeding Unknown Initiation
GAPPS- Prototypic Phenotype Classification
Pathway to Delivery
Caregiver Initiated Clinically Mandated Clinically Discretionary Iatrogenic or no reason Pregnancy Termination No documented indication
Spontaneous Regular Contractions Augmented
GAPPS- Prototypic Phen